Nearly 100 people gathered at the State Building in San
Francisco on Tuesday to hear the latest news on HIV cure research, a field that
has seen remarkable, if slow, progress over the past few years.

Sponsored by the UCSF AIDS Research Institute, the Gladstone
Institutes, and the California Institute for Regenerative Medicine, the town
hall featured researchers from three collaborative efforts funded by the
National Institutes of Health to work on various cure approaches.

A cure for HIV has garnered a great deal of recent
attention, in part due to overly enthusiastic media reports.

"The good news is that these reports are real, but the
sobering news is that making a cure that's safe and available for everyone
remains a huge challenge," said CIRM board member Jeff Sheehy. "We
want to clear up misconceptions and tamp down some of the hype, but we can say
we have solid ground for pragmatic optimism."

The resurgence in optimism is largely attributable to
several "proof-of-concept" cases showing that a functional cure
– once deemed all but impossible – is in fact feasible, explained Dr.
Steven Deeks from UCSF, principal investigator for the Delaney AIDS Research
Enterprise, or DARE, named after the late Project Inform founder Martin
Delaney.

The Berlin Patient – former San Francisco resident
Timothy Brown – remains free of detectable HIV six years after receiving
bone marrow transplants to treat leukemia from a donor with a natural mutation
known as CCR5-delta-32 that makes immune cells resistant to HIV entry.

More recently, a baby in Mississippi born to an HIV-positive
mother was started on combination antiretroviral therapy on the day of birth.
The girl was taken off treatment and lost to follow-up, but when tracked down a
couple years later was found to have no detectable HIV. This appears to be a
case of very early treatment "preventing lifelong infection rather
reversing it," as happened in Brown's case, Deeks said.

Other proof-of-concept cases include a group of 14 people
with HIV in France who started antiretroviral therapy within a few months after
infection. Although they stopped treatment after four or five years, they have
not experienced viral rebound.

Finally, at the International AIDS Society conference this
summer, researchers in Boston reported on two HIV-positive people who received
bone marrow stem cell transplants to treat lymphoma. Unlike Brown, their donors
did not have the CCR5-delta-32 mutation, but they did not experience viral
rebound after experimental interruption of antiretroviral treatment.

"One critical thing about all these [examples] is that
they don't pertain to a typical person with HIV," Deeks cautioned.

Shocking, killing, and protecting cells

Two approaches receiving extensive interest from researchers
are the so-called shock and kill strategy and gene therapy to alter cells.

"Our hypothesis is that viral persistence is driven by
interactions between the virus and the immune system, so a cure may require
interventions aimed not just at the virus but also at the host," said Mike
McCune, also a member of the DARE team.

Shock and kill is the focus of the Collaboratory of AIDS
Researchers for Eradication, or CARE, led by Warner Greene, director of
virology and immunology research at Gladstone.

This approach involves "shocking" or forcing HIV
out of its hiding place in resting reservoir cells. Once the virus is exposed,
the hope is that the immune system will kill off infected cells or give them
the signal to kill themselves.

This is not likely to be accomplished with a single drug,
but rather with a synergistic cocktail, Greene explained. The trick is to
activate T-cells harboring latent HIV, but not to trigger excessive activation
that results in a "cytokine storm" or toxic shock syndrome.

Recent work suggests that the HIV reservoir is larger and
more complex than previously thought, and all cells that harbor latent HIV may
not be "shockable," Greene continued. Furthermore, latently infected
cells do not necessarily die spontaneously after a shock and may need the help
of a therapeutic vaccine.

"It's harder to shock and it's harder to kill," he
said. "At every step we're learning that it's a little more complicated
than we thought it was."

Hans-Peter Kiem from the Fred Hutchinson Cancer Research
Center in Seattle introduced the work of the third collaboration, DefeatHIV,
which is focusing on stem cell transplantation. This includes allogeneic
transplant from donors as well as autologous transplants, in which cells are
modified and reintroduced back into a patient. Gene therapy may be used to make
autologous cells resistant to HIV or to cut out HIV genes integrated into host
cell chromosomes.

CIRM president Alan Trounson described one such approach,
disrupting the gene for CCR5 – one of the gateways HIV uses to enter
cells – essentially mimicking the natural CCR5-delta-32 mutation. Sangamo
BioSciences has already had some success using this method to protect CD4
T-cells, but by altering hematopoietic stem cells, which give rise to all blood
cells, researchers hope to produce an entire protected immune system.

When and where?

Asked about a time frame for cure research to come to
fruition, the researchers were hesitant to give firm estimates.

For different populations it will likely take different
amounts of time, McCune speculated. For children treated at birth like the
Mississippi baby, for example, a cure may come sooner.

"We're where Paul Volberding was in late 1980s with AZT
studies," said Deeks, referring to the pioneering UCSF AIDS researcher.
Early attempts "caused some harm, and not much benefit, but they were the
cornerstone of work that came after."

Forum organizer and community member Matt Sharp, who
participated in Sangamo's T-cell gene therapy trials, urged researchers and
regulators not only to think about the end result, but also about incremental
advances along the way.

"I think it's important that we [look at] some of the
advances that might be made from work done so far," he said. "My
trial reset my CD4 count at a higher level. Let's see what uses we can make of
iterative steps, while keeping mind the ultimate goal."

Asked about their wildest dreams about an HIV cure, all
forum participants agreed that the ultimate goal is to develop approaches that
can be widely implemented in resource-limited settings – particularly in
Africa – where HIV/AIDS is most prevalent.

This will likely require therapies that can be administered
wherever patients are located and will work in the body, as opposed to current
methods that require cells to be removed, modified in a laboratory, and
returned to the patient.

"The only hope for Africa is a cure," Greene
concluded. "The world is not able and willing to put everybody on
antiretroviral therapy for the rest of their lives. Whatever the cure is, it
has to be safe, it has to be scalable, and it has to be usable in developing
countries."